This invention relates to novel substituted cyclopentane and cyclopentene compounds and derivatives thereof useful as neuraminidase inhibitors, to pharmaceutical compositions containing said compounds useful for the prevention, treatment or amelioration of viral, bacterial and other infections, and to methods of using said compounds. The present invention is also concerned with novel intermediates or precursors for producing the novel substituted cyclopentane and cyclopentene compounds of the present invention.
Despite the wealth of information available, influenza remains a potentially devastating disease of man, lower mammals, and birds. No effective vaccine exists and no cure is available once the infection has been initiated.
Influenza viruses consist of eight pieces of single stranded RNA, packaged in orderly fashion within the virion. Each piece codes for one of the major viral proteins. The replication complex is enclosed with a membrane composed of matrix protein associated with a lipid bilayer. Embedded in the lipid bilayer are two surface glycoprotein spikes, hemagglutinin (HA) and the enzyme neuraminidase (NA). All the viral genes have been cloned and the three dimensional structures of the surface glycoproteins have been determined.
Influenza viruses continually undergo antigenic variation in the two surface antigens, HA and NA, toward which neutralizing antibodies are directed. For this reason, vaccines and a subject""s natural immune system have not been very effective. Attention is now being directed to finding other potential antiviral agents acting at others sites of the virion. This invention is directed to novel compounds which are useful in inhibiting the viral surface enzyme NA.
Furthermore, many other organisms carry also NA. Many of these NA-possessing, organisms are also major pathogens of man and/or mammals, including Vibraeo Cholerae, Clostridium perfringes, Streptococcus pneumonia, Arthrobacter sialophilas, and other viruses, such as parainfluenza virus, mumps virus, newcastle disease virus, fowl plague virus, and Sendai virus. Compounds of this invention are also directed to inhibiting NA of these organisms.
In viruses, NA exists as a tetramer made of four roughly spherical subunits and a centrally-attached stalk containing a hydrophobic region by which it is embedded in the organism""s membrane. Several roles have been suggested for NA. The enzyme catalyzes cleavage of the xcex1-Ketosidic linkage between terminal sialic acid and the adjacent sugar residue. Removal of the sialic acid lowers the viscosity and permits access of the virus to the epithelial cells. NA also destroys the HA receptor on the host cell, thus allowing elution of progeny virus particles from infected cells.
Research indicates that the active site for influenza neuraminidase remains substantially unchanged for the major strains of influenza. For example, a comparison of sequences from influenza A subtypes and influenza B shows conserved residues with crucial structures and functional roles. Even though the sequence homology is only about 30%, many of the catalytic residues are conserved. Furthermore, the three-dimensional structures of influenza A and B neuraminidases have been determined. Superposition of the various structures shows remarkable structural similarity of the active site. Since the active site amino acid residues are conserved in all known influenza A neuraminidases that have been sequenced so far, an inhibitor that is effective against different strains of influenza A and/or B neuraminidase can be designed based on the three dimensional structure of neuraminidase.
In general, the role of NA is thought to be for the mobility of the virus both to and from the site of infections. Compounds that inhibit neuraminidase""s activity may protect a subject from infection and/or cure a subject once infection has set in. It is a further object of this invention to provide a method of using compounds of this invention for treating and/or curing a viral infection.
Analogues of neuraminic acid, such as 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA) and its derivatives are known to inhibit HA in vitro; however, these compounds are inactive in vivo. Palese and Schulman, IN CHEMOPROPHYLAXIX AND VIRUS INFECTIONS OF THE UPPER RESPIRATORY TRACT, Vol. 1 (J. S. Oxford, Ed.), CRC Press, 1977, at PS 189-205.
Von Itzstein et al. describes cyclohexane analogs of xe2x88x9d-D-neuraminic acid of the formula 
Wherein:
A is O, C or S in formula (a), and N or C in formula (b);
R1 is CO2H, PO3H2, NO2, SO2H, SO3H, tetrazolyl-, CH2CHO, CHO, or CH(CHO)2;
R2 is H, OR6, F, Cl, Br, CN, NHR6, SR6 or CH2X, where X is NHR6 halogen or OR6;
R3 and R3xe2x80x2 are H, CN, NHR6, SR6, xe2x95x90NOR6, OR6, guanidino, NR6;
R4 is NHR6, SR6, OR6, CO2R6, NO2, C(R6)3, CH2CO2R6, CH2NO2 or CH2NHR6;
R5 is CH2YR6, CHYR6CH2YR6 or CHYR6CHYR6CH2YR6;
R6 is H, acyl, alkyl, allyl, or aryl;
Y is O, S, NH, or H;
and pharmaceutical salts thereof, useful as antiviral agents.
In addition, certain benzene derivatives are suggested in U.S. Pat. No. 5,453,533 as being inhibitors of influenza virus neuraminidase and various others are disclosed in U.S. Pat. No. 5,602,277. Yamamoto et al. describe various sialic acid isomers as having inhibitory activity against neuraminidase in Synthesis of Sialic Acid Isomers With Inhibitory Activity Against Neuraminidase, Tertrahedron Letters, Vol. 33, No. 39, pp. 5791-5794, 1992.
WO 96/26933 to Gilead sciences, Inc. describes certain 6-membered ring compounds as possible inhibitors of neuraminidase.
However, none of these references disclose the cyclopentane and cyclopentene derivatives of the present invention.
An aspect of the present invention is directed to compounds represented by the formulae: 
wherein
U is CH, O, or S;
Z is xe2x80x94C(R2)(R3), xe2x80x94CHxe2x80x94N(R2)(R3), C(R3)[(CH2)nR2], CHxe2x80x94C(R3)(R8)(CH2)nR2, C[(CH2)nR2]xe2x80x94[CH(R3)(R8)], C[(R3)][CH[(CH2)nR2](R8)];
R1 is H, (CH2)nOH, (CH2)nNH2, (CH2)nNR10R11, (CH2)nOR11, (CH2)nSR11, or (CH2)n halogen
R9 is (CH2)nCO2H, (CH2)nSO3H, (CH2)nPO3H2, (CH2)nNO2, CH(SCH3)3, esters thereof, or salts thereof;
or R1 R9 together represent 
R2 is H, NHC(O)R5, NHC(S)R5, NHSO2R5, C(O)NHR5, SO2NHR5, CH2S(O)R5, or CH2SO2R5 
R3 and R8 individually is H, (CH2)nC(O)R10, (CH2)nCO2R10, (CH2)mOR10, CH(OR10)CH(R10)m, C(O)N(R10)m, C(O)N(OR10)R10, (CH2)nN(R10)m, CH(R10)m, (CH2)n(R10)m, CH2CH(OR10)CH2OR10, CH(OR10)CH(OR10)CH2OR10, CH2OR10, CH(OR10)CH2NHR10, CH2CH(OR10)CH2NHR10, CH(OR10)CH(OR10)CH2NHR10, C(xe2x95x90NR10)N(R10)m, NHR10, NHC(xe2x95x90NR10)N(R10)m, (CH2)mxe2x80x94Xxe2x80x94Wxe2x80x94Y, CH2CH(Xxe2x80x94Wxe2x80x94Y)CH2OR10, CH(Xxe2x80x94Wxe2x80x94Y)CH(OR10)CH2OR10, CH(Xxe2x80x94Wxe2x80x94Y)CH2(OR10), CH(OR10)CH(Xxe2x80x94Wxe2x80x94Y)CH2OR10, CH(OR10)CH2(Xxe2x80x94Wxe2x80x94Y), CH2CH(Xxe2x80x94Wxe2x80x94Y)CH2NHR10, CH(Xxe2x80x94Wxe2x80x94Y)CH(OR10)CH2NHR10, CH(Xxe2x80x94Wxe2x80x94Y)CH2(NHR10), CH(OR10)CH(Xxe2x80x94Wxe2x80x94Y)CH2NHR10, or CH(NHR10)CH2(Xxe2x80x94Wxe2x80x94Y);
provided that at least one of R2, R3, and R8 is other than H;
R4 is H, (CH2)nOH, (CH2)nOR11, (CH2)nOC(O)R11, (CH2)nNHC(NR11)NHR11, (CH2)nNR10R11, (CH2)nNH2, (CH2)nC(xe2x95x90NH)(NH2), (CH2)nNHC(xe2x95x90NR11)NH2, (CH2)nNHC(xe2x95x90NR7)NH2, (CH2)nCN, (CH2)nN3, C(xe2x95x90NH)NH2, C(NR7)NH2, or C(NR11)NH2;
R5 is H, lower alkyl, cyclo alkyl, halogen substituted alkyl, aryl, substituted aryl, or CF3;
R7 is H, (CH2)nOH, (CH2)nCN, (CH2)nNH2, or (CH2)nNO2;
R10 is H, lower alkyl, lower alkylene, branched alkyl, cyclic alkyl, (CH2)n aromatic, (CH2)n substituted aromatic, or when m is 2 both R10 groups can also be interconnected to form an N substituted heterocyclic ring, or other 5 or 6 membered heterocyclic ring;
R11 is lower alkyl, branched alkyl, (CH2)m aromatic, SO2R10, C(O)R10, or C(O)OR10;
R12 and R13 is H, (CH2)nOH, (CH2)nNH2, (CH2)nNR10R11, (CH2)nOR11, (CH2)nF, (CH2)nOC(O)R11, (CH2)nNHC(O)R11, or Xxe2x80x94Wxe2x80x94Y;
m is 1 or 2;
n is 0-4;
p is 0 or 1;
X is O, S, CH2,or NH;
W is a spacer group made up of a chain of 1 to 100 atoms, and optionally also comprising of substituted carbon and/or nitrogen atoms and optionally including oxygen or sulphur atoms; and
Y is H, OH, SH, NH2, CHxe2x95x90O, CHxe2x95x90CH2, CO2H, CONHNH2, or a protected form of one of these end functionalities;
and pharmaceutically aceptable salts thereof.
The present invention is also concerned with compositions for inhibiting influenza virus neuraminidase comprising a pharmaceutically acceptable carrier and an amount effective for inhibiting influenza virus nueraminidase of a compound as defined above.
A further aspect of the present invention involves a method for inhibiting influenza virus that comprises administering to a patient in need thereof a compound as defined above in a amount effective for inhibiting influenza virus nueraminidase.
A still further aspect of the present invention is concerned with treating influenza virus infection comprising administering to a patient in need thereof a compound as defined above in an amount effective for inhibiting influenza virus nueramindase.
Another aspect of the present invention relates to intermediates represented by the following formulae: 
Wherein R4 and R9 are the same defined above; and 
Wherein R14 individually is H, O, (CH2)nCO2H, (CH2)nSO3H, (CH2)nPO3H2, (CH2)nNO2, CH(SCH3)3, 
esters thereof or salts thereof and provided at least one of R14 is H, and R3 and R4 are as defined above.
An aspect of the present invention is directed to compounds represented by the formulae: 
wherein
U is CH, O, or S;
Z is xe2x80x94C(R2)(R3), xe2x80x94CHxe2x80x94N(R2)(R3), C(R3)[(CH2)nR2], CHxe2x80x94C(R3)(R8)(CH2)nR2, C[(CH2)nR2]xe2x80x94[CH(R3)(R8)], C[(R3)][CH[(CH2)nR2](R8)];
R1 is H, (CH2)nOH, (CH2)nNH2, (CH2)nNR10R11, (CH2)nOR11, (CH2)nSR11, or (CH2)n halogen
R9 is (CH2)nCO2H, (CH2)nSO3H, (CH2)nPO3H2, (CH2)nNO2, CH(SCH3)3, esters thereof, or salts thereof;
or R1 R9 together represent 
R2 is H, NHC(O)R5, NHC(S)R5, NHSO2R5, C(O)NHR5, SO2NHR5, CH2S(O)R5, or CH2SO2R5 
R3 and R8 individually is H, (CH2)nC(O)R10, (CH2)nCO2R10, (CH2)mOR10, CH(OR10)CH(R10)m, C(O)N(R10)m, C(O)N(OR10)R10, (CH2)nN(R10)m, CH(R10)m, (CH2)n(R10)m, CH2CH(OR10)CH2OR10, CH(OR10)CH(OR10)CH2OR10, CH2OR10, CH(OR10)CH2NHR10, CH2CH(OR10)CH2NHR10, CH(OR10)CH(OR10)CH2NHR10, C(xe2x95x90NR10)N(R10)m, NHR10, NHC(xe2x95x90NR10)N(R10)m, (CH2)mxe2x80x94Xxe2x80x94Wxe2x80x94Y, CH2CH(Xxe2x80x94Wxe2x80x94Y)CH2OR10, CH(Xxe2x80x94Wxe2x80x94Y)CH(OR10)CH2OR10, CH(Xxe2x80x94Wxe2x80x94Y)CH2(OR10), CH(OR10)CH(Xxe2x80x94Wxe2x80x94Y)CH2OR10, CH(OR10)CH2(Xxe2x80x94Wxe2x80x94Y), CH2CH(Xxe2x80x94Wxe2x80x94Y)CH2NHR10, CH(Xxe2x80x94Wxe2x80x94Y)CH(OR10)CH2NHR10, CH(Xxe2x80x94Wxe2x80x94Y)CH2(NHR10), CH(OR10)CH(Xxe2x80x94Wxe2x80x94Y)CH2NHR10, or CH(NHR10)CH2(Xxe2x80x94Wxe2x80x94Y);
provided that at least one of R2, R3, and R8 is other than H;
R4 is H, (CH2)nOH, (CH2)nOR11, (CH2)nOC(O)R11, (CH2)nNHC(NR11)NHR11, (CH2)nNR10R11, (CH2)nNH2, (CH2)nC(xe2x95x90NH)(NH2), (CH2)nNHC(xe2x95x90NR11)NH2, (CH2)nNHC(xe2x95x90NR7)NH2, (CH2)nCN, (CH2)nN3, C(xe2x95x90NH)NH2, C(NR7)NH2, or C(NR11)NH2;
R5 is H, lower alkyl, cyclo alkyl, halogen substituted alkyl, aryl, substituted aryl, or CF3;
R7 is H, (CH2)nOH, (CH2)nCN, (CH2)nNH2, or (CH2)nNO2;
R10 is H, lower alkyl, lower alkylene, branched alkyl, cyclic alkyl, (CH2)n aromatic, (CH2)n substituted aromatic, or when m is 2 both R10 groups can also be interconnected to form an N substituted heterocyclic ring, or other 5 or 6 membered heterocyclic ring;
R11 is lower alkyl, branched alkyl, (CH2)m aromatic, SO2R10, C(O)R10, or C(O)OR10;
R12 and R13 is H, (CH2)nOH, (CH2)nNH2, (CH2)nNR10R11, (CH2)nOR11, (CH2)nF, (CH2)nOC(O)R11, (CH2)nNHC(O)R11, or Xxe2x80x94Wxe2x80x94Y;
m is 1 or 2;
n is 0-4;
p is 0 or 1;
X is O, S, CH2, or NH;
W is a spacer group made up of a chain of 1 to 100 atoms, and optionally also comprising of substituted carbon and/or nitrogen atoms and optionally including oxygen or sulphur atoms; and
Y is H, OH, SH, NH2, CHxe2x95x90O, CHxe2x95x90CH2, CO2H, CONHNH2, or a protected form of one of these end functionalities;
and pharmaceutically aceptable salts thereof.
The present invention also relates to intermediates represented by the following formulae: 
wherein R4 and R9 are the same defined above; and 
wherein R14 individually is H, O, (CH2)nCO2H, (CH2)nSO3H, (CH2)nPO3H2, (CH2)nNO2, CH(SCH3)3, 
esters thereof or salts thereof and provided at least one of R14 is H, and R3 and R4 are as defined above.
The lower alkyl groups contain 1 to about 8 carbon, and preferably 1 to about 3 carbon atoms, and can be straight, branched-chain or cyclic saturated aliphatic hydrocarbon groups.
Examples of suitable alkyl groups include methyl, ethyl, and propyl. Examples of branched alkyl groups include isopropyl and t-butyl. Examples of suitable cyclic aliphatic groups typically contain 3-8 carbon atoms and include cyclopentyl and cyclohexyl. The aromatic or aryl groups are preferably phenyl or alkyl substituted aromatic groups (aralkyl) such as phenyl C1-3 alkyl such as benzyl, or halo substituted aryl groups.
Examples of substituted cycloalkyl groups include cyclic aliphatic groups typically containing 3-8 carbon atoms in the ring substituted with alkyl groups typically having 1-6 carbon atoms and/or hydroxy group. Usually 1 or 2 substituted groups are present.
The esters are typically lower alkyl esters having 1 to about 12 carbon atoms and preferably 1 to about 3 carbon atoms and aryl esters containing 6 to 14 carbon atoms. The alkyl esters can be straight-chain, branched-chain or cyclic saturated aliphatic hydrocarbons.
Examples of some alkyl esters are methyl, ethyl, propyl, isopropyl, t-butyl, cyclopentyl and cyclohexyl esters. The aryl esters are preferably phenyl or alkyl substituted aromatic esters (alkaryl) including C1-3 alkyl substituted phenyl such as benzyl.
The lower alkylene group can be straight, branched chain or cyclic unsaturated hydrocarbon group and contains 2-8 carbon atoms and preferably 2-3 carbon atoms. Examples of alkylene groups are vinyl, 1-propenyl, allyl, isopropenyl, 2-methyl-2-propenyl and cyclopentenyl.
The N-heterocyclic rings contain 3-7 atoms in the ring. The heterocyclic rings can be substituted such as with a lower alkyl group. Examples of suitable heterocyclic groups are pyrrolidino, azetidino, piperidino, 3,4-didehydropiperidino, 2-methylpiperidino and 2-ethylpiperidino.
Suitable spacer groups W include, but are not limited to, linear peptides, oligosaccharides, polyols, polyethylene glycol groups, hydrocarbon groups and hydrocarbon groups linked together with oxygen or sulphur atoms, or with carbonyl, amido, urea or hydrazide functionalities. Spacer groups W may also comprise combinations of these various groups. The spacer groups can be straight or branched chain.
Suitable protecting groups for functionality Y include, but are not limited to, esters of the OH, SH, CO2H groups, carbamates of NH2 and CONHNH2 groups, and acetals of the CHxe2x95x90O group.
As used herein, the term xe2x80x9chydrocarbon groupxe2x80x9d includes saturated and unsaturated straight or branched hydrocarbon groups, including aryl groups, and combinations of such groups.
Pharmaceutically acceptable salts of the compounds of formula (I) include those derived from pharmaceutically acceptable, inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toluene-p-sulphonic, tartaric, acetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic, trifluoroacetic and benzenesulphonic acids.
Salts derived from appropriate bases include alkali such as sodium and ammonia.
It is of course understood that the compounds of the present invention relate to all optical isomers and stereo-isomers at the various possible atoms of the molecule.
Examples of some particular formulae within the scope of this invention are represented by the following: 
The naming system which has been used herein for the compounds of the following type is as follows: 
In some cases xcex1 and xcex2 have been used to show that these groups are trans to each other. These are the cases when we have more than two substituents on cyclopentane ring and only two are fixed.
In fused cyclopent[d]isoxazole system, the numbering is as follows: 
Examples of some specific compounds and intermediates according to the present application are identified in Examples 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208 and 209.
The following schemes illustrate methods for preparing compounds of the present invention. 
In addition, an important intermediate to the present invention, compounds 125-136, can be prepared by reacting a cyclopentene of the formula 
with corresponding nitrile oxide (produced from phenyl isocyanate, and a nitroalkane in the presence of triethylamine or from chloro-oxime and triethylamine) to produce an cyclopent[d]isoxazole ring system. The product can then be hydrogenated in the presence of a PtO2 in an alcohol along with HCl to open the ring and form a corresponding amino compound.
Also, process for preparing compounds of the present invention can be found in U.S. patent application Ser. No. 60/085,252 filed May 13 1998, entitled xe2x80x9cPreparation of substituted Cyclopentane and Cyclopentene Compounds and Certain Intermediatesxe2x80x9d to Chand et al, entire disclosure of which is incorporated herein by reference.